Interaction of sulfonamide and sulfone compounds with Toxoplasma gondii dihydropteroate synthase.
Toxoplasma gondii is a common protozoan disease that often causes life-threatening disease, particularly among patients with the acquired immunodeficiency syndrome. This study demonstrates that the dihydropteroate synthase in T. gondii is kinetically distinct from the enzyme characterized from other sources and can be highly purified with a high yield using sequential dye-affinity chromatography. Conditions have been identified that allow for stabilization of the purified enzyme, and its physical characteristics have been elucidated. The molecular weight of the native protein was 125,000 and the protein appeared to contain both dihydropteroate synthase and 6-hydroxymethyl-dihydropterin pyrophosphokinase activities. The sulfonamide class of compounds vary in inhibitory potency by more than three orders of magnitude. Sulfathiazole, sulfamethoxazole, and sulfamethazine, with 50% inhibitory concentrations (IC50's) of 1.7, 2.7, and 5.7 microM, respectively, represent the most potent of this class of inhibitors. Several sulfone analogues, including dapsone, were identified as highly potent inhibitors with IC50's less than 1 microM. The results of these cell-free experiments were corroborated by investigating the metabolic inhibition produced by the various inhibitors in intact organisms. The qualitative and quantitative relations among the inhibitors were preserved in both the cell-free and intact cell assay systems. These studies suggest that the sulfones may be important therapeutic agents for the treatment of toxoplasmosis.
Allegra
C J
CJ
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Boarman
D
D
Kovacs
J A
JA
Morrison
P
P
Beaver
J
J
Chabner
B A
BA
Masur
H
H
D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000818:Animals; D004094:Dihydropteroate Synthase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D004795:Enzyme Stability; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects / Q000201:enzymology*; D014166:Transferases / Q000037:antagonists & inhibitors*
D013449:Sulfonamides; D013450:Sulfones; D014166:Transferases; D004094:Dihydropteroate Synthase; D010129:4-Aminobenzoic Acid